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ModeratorNeil Love, MD

Faculty

Oncology Grand RoundsNew Agents and Strategies in Urothelial Bladder Carcinoma

Thursday, June 18, 20205:00 PM – 6:30 PM ET

Arjun Balar, MDAnastassia Daskalova, NP

Peter H O’Donnell, MDSusan K Roethke, CRNP, MSN, ANP-BC, AOCNP

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Oncology Grand RoundsNew Agents and Strategies in

Chimeric Antigen Receptor T-Cell TherapyTuesday, June 23, 20205:00 PM – 6:30 PM ET

Krishna Komanduri, MD Nikhil C Munshi, MDSattva S Neelapu, MD

Tiffany A Richards, PhD, ANP-BC, AOCNPElizabeth Zerante, AGACNP-BC

Jointly provided by


Faculty

Oncology Grand RoundsNew Agents and Strategies in Urothelial Bladder Carcinoma

Thursday, June 18, 20205:00 PM – 6:30 PM ET

Arjun Balar, MDAnastassia Daskalova, NP

Peter H O’Donnell, MDSusan K Roethke, CRNP, MSN, ANP-BC, AOCNP

Agenda

Module 1: Overview of Urothelial Bladder Cancer (UBC) ManagementCase Presentation: Ms Roethke — 85-year-old widower and retired automotive mechanic

Module 2: Anti-PD-1/PD-L1 Antibodies for Patients with Nonmetastatic UBC

Module 3: Risks and Benefits of Immune Checkpoint Inhibitors in Advanced UBCCase Presentation: Ms Daskalova — 78-year-old woman with a PMH of cervical cancer

Module 4: Integration of FGFR-Directed Therapy into Current UBC Management AlgorithmsCase Presentation: Ms Roethke — 62-year-old auto body repairman

Module 5: Antibody-Drug Conjugates in UBCCase Presentation: Ms Roethke — 70-year-old married man and retired telephone technician

Module 6: Management of UBC in the Era of COVID-19Case Presentation: Ms Daskalova — 63-year-old man

Module 1: Overview of Urothelial Bladder Cancer (UBC) Management

When was the last time you encountered a patient with bladder cancer?

a. Within the past week

b. Between 1 week and 1 month ago

c. Between 1 month and 6 months ago

d. Between 6 months and 1 year ago

e. More than 1 year ago

f. I have not encountered a patient with bladder cancer in my practice

Which of the following is the most significant risk factor for the development of bladder cancer?

a. Obesity

b. Smoking

c. Female sex

d. I don’t know

Overview of Bladder Cancer

• Patient profile– Median age at diagnosis: 73 years

– 76% male

– Smoking is the most well-established risk factor (47% of all cases in the US)

• Natural history– Non-muscle-invasive

– Muscle-invasive

– Metastatic

• Cystectomy and ileal conduit/stoma management

• Neoadjuvant and adjuvant chemotherapy

ACS Cancer Facts & Figures 2020; www.cancer.org.

With permission from Terese Winslow LLC

High-Risk Non‒Muscle-Invasive BC• High-risk (HR) NMIBC is defined as any carcinoma in situ (CIS), T1 tumor, and/or

high-grade Ta tumor

• Standard-of-care therapy for HR NMIBC is TURBT and intravesical Bacillus Calmette-Guérin (BCG)

– Although there is a high rate of complete response (70%) to initial therapy, most patients with high-risk disease do not maintain response

§ 30% of patients experience recurrence within 1 year

§ 40% of patients at high risk progress to muscle-invasive disease

§ 20%-30% of patients progress to metastatic disease

• BCG unresponsive disease – standard of care is cystectomy

• With the lack of a suitable comparator, single-arm designs testing novel agents are thought to be acceptable in the BCG-unresponsive population

• World-wide BCG shortage

Cumberbatch MGK et al. Eur Urol. 2018;74:784-795. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines):bladder cancer (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed January 7, 2019. Hemdan T et al. J Urol. 2014;191:1244. Herr HW et al. Urol Oncol. 2015;33:108.e1-4. 5. Anastasiadis A et al. Ther Adv Urol. 2012;4:13-32. US Department of Health and Human Services. BCG-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment—Guidance for industry. February 2018. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm529600.pdf. Accessed February 5, 2019. Babjuk M et al. Eur Urol. 2017;71:447-461. Courtesy of Arjun V. Balar, MD

85-year-old Widower and Prior Smoker with PMH of stage IV CKD, HTN, GERD, Anemia of Chronic Disease and Chronic Back Pain (from the practice of Ms Roethke)• 5/2019: pT1 multifocal, high-grade invasive urothelial cancer (UC), with gross hematuria and

clot retention

– PCNU due to hydronephrosis at initial TURBT

• 6/2019, 8/2019: Recurrent non-muscle invasive disease à BCT

• 11/2019: Admitted with Hgb: 5.5

– TURBT: Invasive high-grade UC, with invasion of muscularis propria• Not eligible for platinum-based chemo due to CKD, hearing loss, frailty

• Molecular testing: PD-L1 CPS: 10

• 12/2019: Pembrolizumab 200mg Q3W x 6

– Changed to 400mg Q6W during COVID-19 pandemic

– Imaging: Smaller mass, but not contrast CT• 5/2020 Cystoscopy to change ureteral stent: No visible tumor

Agenda







When was the last time you encountered a patient with bladder cancer receiving an anti-PD-1/PD-L1 antibody?






f. I have not encountered a patient with bladder cancer receiving an anti-PD-1/PD-L1 antibody in my practice

• PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function

– Anti-PD-1 antibodies bind PD-1 receptors on T cells and disrupts negative signaling triggered by PD-L1/PD-L2 to restore T-cell antitumor function

– Anti-PD-L1 antibodies bind PD-L1 receptors

MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

T-cellreceptorT-cell

receptor

PD-L1PD-L2

PD-L2

MHC

CD28 B7

T cell

NFκBOther

PI3KDendritic

cellTumor cell

IFNγ

IFNγR

Shp-2Shp-2

Anti-PD-1/PD-L1 Antibodies: Mechanism of Action

KEYNOTE-057: Single-Arm, Open-Label Phase 2 Study (NCT02625961)

Patients• HR NMIBC patients unresponsive to

BCG who decline to undergo or are ineligible for cystectomy

• Patients with papillary disease must have fully resected disease at study entry

• 2 cohorts

– Cohort A (n = 130): CIS with or without papillary disease (high-grade Ta or T1)

– Cohort B (n = 130): papillary disease (high-grade Ta or any T1) without CIS

Pembrolizumab200 mg Q3W

Evaluations with cystoscopy, cytology, ±biopsy Q12W × 2 years,

then Q24W × 2 years and once yearly

thereafterand

CTU Q24W × 2 years or more frequently as clinically indicated

If HR NMIBC present at any assessment Discontinue treatment; enter survival follow-up

If no persistence or recurrence of HR NMIBC at any assessment

Continue assessments and pembrolizumab until

recurrence of HR NMIBC, PD, or 24 months of treatment complete

Primary End Points• CR (absence of HR

NMIBC) in cohort A• DFS in cohort B

Secondary End Points• CR (absence of any

disease: high-risk or low-risk NMIBC) in cohort A

• DOR in cohort A• Safety/tolerability

Courtesy of Arjun V. Balar, MD

1. Balar A et al. ASCO GU 2019. Abstract 350. 2. Balar A. FDA ODAC submission 2019.

Duration of Complete Response is Clinically Meaningful

No. at Risk 39 36 27 18 18 14 10 5 4 2 1 0

0

20

40

60

80

100

-1 2 5 8 11 14 17 20 23 26 29 32

Rem

aini

ng in

Com

plet

e R

espo

nse,

%

Duration of CR, mo (Begins From Initial CR Assessment)

| Censored

0 3 6 9 12 15 18 21 24 27 30 33

Time CR achieved

Median DOR (range): 16.2 (0.0+ to 30.4+)

• Of 96 patients, 39 achieved CR at first disease assessment

• Patients not in CR at first disease assessment came off treatment

12-mo DOR landmark• ≈15 mo from start of therapy• 57% by Kaplan Meier estimate• Number of patients with observed DOR ≥12 mo was

– 18/39 (46%) of initial complete responders – 19% of all treated patients (n = 96)


IMvigor010: Primary Analysis from A Phase III Randomized Study of Adjuvant Atezolizumab (Atezo) versus Observation (Obs) in High-Risk Muscle-Invasive Urothelial Carcinoma (MIUC)

Hussain MH et al.ASCO 2020;Abstract 5000.

IMvigor010 Phase III Trial Schema

Hussain MH et al. ASCO 2020; Abstract 5000.

IMvigor010: Disease-Free Survival (DFS) in ITT Population

Hussain MH et al. ASCO 2020; Abstract 5000.

Agenda







Module 3: Risks and Benefits of Immune Checkpoint Inhibitors in Advanced UBC

A long time ago, in a galaxy far far away?• 1985 - MVAC reported• 1997 - Gemcitabine

reported to have activity– GC found comparable to

MVAC in 2000• Response rates:– 50-55% tumor regression– additional 33% with

stable disease• Median PFS 7.5 months• OS 14 months

Sternberg et al., J Urol (1985)Stadler et al., JCO (1997)von der Maase et al., JCO (2000)Courtesy of Peter H O’Donnell, MD

Current Treatment ParadigmsMetastatic Urothelial Ca

• Cisplatin eligible– gem/cis

• Cisplatin ineligible– immunotherapy (pembro or atezo) if PD-L1+– gem/carbo

• Chemotherapy unfit– immunotherapy (pembro or atezo)

• Platinum refractory– 5 immunotherapies (pembro level 1 evidence)

Courtesy of Peter H O’Donnell, MD

Response Rates to First-Line Therapy for Metastatic Urothelial Carcinoma

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DD MVACSternbergEJC 2006

Gem Cisvon der Masse

JCO 2000

Gem CarboDe SantisJCO 2012

PembrolizumabVuky

ASCO 2018

AtezolizumabBalar

ASCO 2018

CISPLATIN ELIGIBLE CISPLATIN INELIGIBLE

Partial responseComplete response

IMvigor210 Cohort 1 Study Design: First-Line Treatment

a PD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded.1. Balar A et al. 2016 American Society of Clinical Oncology Annual Meeting (ASCO 2016). Abstract LBA4500. 2. Balar AV et al. Lancet. 2017;389:67-76.

Treatment

Patients

Cohort 1 (n = 119)First-line

cisplatin-ineligible

Atezolizumab 1,200 mg IV every 3 wk until

RECIST 1.1 progression

Atezolizumab 1,200 mg IV every 3 wk until

loss of clinical benefit

Cohort 2 (n = 310)Platinum-treated mUC

• Primary endpoints: confirmed ORR by RECIST 1.1 by central IRF

• Key secondary endpoints: DOR, PFS, OS, and safety

Cohort 1: Specific Inclusion Criteria • No prior treatment for mUC (>12 mo since perioperative chemoTx)• ECOG PS 0-2• Cisplatin ineligibility based on ≥1 of the following

─ Renal impairment: GFR <60 and >30 mL/min─ Grade ≥2 hearing loss or peripheral neuropathy─ ECOG PS 2

• Inoperable locally advanced or metastatic UC

• Predominantly UC histology

• Tumor tissue evaluable for PD-L1 testinga


Pembrolizumab 200 mg every 3 wk

• Primary endpoints: ORR in all patients and ORR in patients with PD-L1–positive tumors• Secondary endpoints: DOR, PFS, OS, and ORR in all patients, PD-L1–positive, and PD-L1–high expressing patients;

safety and tolerability; establishing an assay cutpoint for high PD-L1 expression in first 100 patients, with validation in second 250 patients

KEYNOTE-052: Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced UC1

N = 350• Advanced urothelial cancer• No prior chemotherapy for metastatic disease• ECOG PS 0-2• Ineligible for cisplatin based on ≥1 of the following

– CrCl <60 mL/min– ECOG PS 2 – Grade ≥2 neuropathy or hearing loss– NYHA class III CHF

42% were ECOG PS 249% aged ≥75 y

85% had visceral metastases49% had renal impairment1. Balar AV et al. Lancet. 2017;18:1483-1492.

DemographicsCourtesy of Arjun V. Balar, MD

• Pembrolizumab is indicated for the treatment of patients with locally advanced or metastatic UC who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status1

• Atezolizumab is indicated for the treatment of patients with locally advanced or metastatic UC who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1–stained tumor-infiltrating immune cells covering ≥5% of the tumor area), as determined by an FDA-approved test, or are not eligible for any platinum-containing therapy regardless of PD-L1 status2

Regulatory Updates for PD-1/PD-L1 Therapy in Advanced Cis-Ineligible UC

Requires the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue


IMvigor130 study design

Arm CPlacebo + platinum/gem

Arm AAtezo + platinum/gem

Arm BAtezo monotherapy

• Locally advanced or mUC• No prior systemic therapy in the metastatic setting

• ECOG PS ≤ 2• 1L platinum-eligible• N = 1200• Randomised 1:1:1

Co-primary endpoints:• INV-assessed PFSa and OS (Arm A vs C) • OS (Arm B vs C, hierarchical approach)

Stratification factors:• PD-L1 IC status (IC0 vs IC1 vs IC2/3)• Bajorin risk factor score including KPS < 80% vs

≥ 80% and presence of visceral metastases (0 vs 1 vs 2 and/or patients with liver metastases)

• Investigator choice of plt/gem (cisplatin + gem or carboplatin + gem)

Key secondary endpoints:• INV-ORRa and DOR• PFSa and OS (Arm B vs C; PD-L1 IC2/3

subgroup)• Safety

a per RECIST 1.1.

Adapted from Grande et al. ESMO 2019Courtesy of Jonathan E Rosenberg, MD

Maintenance Avelumab + Best Supportive Care (BSC) versus BSC Alone After Platinum-Based First-Line (1L) Chemotherapy in Advanced Urothelial Carcinoma (UC): JAVELIN Bladder 100 Phase III Interim Analysis

Powles T et al.ASCO 2020;Abstract LBA1 (Plenary)

JAVELIN Bladder 100 Phase III Study Schema

Powles T et al. ASCO 2020;Abstract LBA1.

JAVELIN Bladder 100: OS in the Overall Population


JAVELIN Bladder 100: OS in the PD-L1+ Population


FDA-Approved Anti-PD-1/PD-L1 Antibodies for Patients with Progressive Metastatic UBC

Agent Initial approval date

Atezolizumab (PD-L1) May 2016

Nivolumab (PD-1) February 2017

Durvalumab (PD-L1) May 2017

Avelumab (PD-L1) May 2017

Pembrolizumab (PD-1) May 2017

The Constellation of irAEs

Hypophysitis

Thyroiditis/hypothyroidism

Rash and vitiligoHepatitis

EnteritisColitis

Pneumonitis

Myocarditis

Uveitis

Encephalitis, aseptic meningitis

Thrombocytopenia/anemia

Dry mouth/mucositis

PancreatitisAutoimmune diabetes

Nephritis

NeuropathyArthralgia

Vasculitis

Adrenal insufficiency


78-year-old woman with a PMH of cervical cancer, controlled HTN (from the practice of Ms Daskalova)

• 4/2019: Urinary urgency, frequency and hematuria past few months

– CT AP: Bladder wall thickening, no lymphadenopathy or visceral mets

• 5/2019: TURBT: High-grade muscle-invasive urothelial cancer

• 6/2019: Cystectomy (pT4N2 – 8/21 nodes+), with negative margins à pt declines adjuvant therapy, opts for surveillance

• 1/2020: MRI AP and CT chest: Extensive recurrent tumor in cystectomy bed, new liver and lung mets, and retroperitoneal, pelvic and inguinal lymphadenopathy– Symptomatic: Pain, fatigue, weight loss, insomnia

• Cisplatin-ineligible based on kidney function (Cr Cl <60 [37])

– PDL1 status: Low

– BRCA2 and TP53 mutations

• Carboplatin + gemcitabine x 6 à Significant response • Plan to enroll on a clinical trial (“as maintenance”) with immunotherapy + personalized vaccine

Agenda







Module 4: Integration of FGFR-Directed Therapy into Current UBC Management Algorithms

When was the last time you encountered a patient with bladder cancer receiving erdafitinib?






f. I have not encountered a patient with bladder cancer receiving erdafitinib in my practice

FGFR Inhibition

modified from Sethakorn and O’Donnell, BJUI (2016)

Drug inhibitor


BLC2001: A Phase II Study of the Oral Pan-FGFR (1-4) Inhibitor Erdafitinib

Siefker-Radtke AO et al. Proc ASCO 2018;Abstract 4503; www.clinicaltrials.gov; Accessed May 24, 2019 (NCT02365597).

Eligibility• Metastatic or unresectable

locally advanced UC• Prior ICI allowed• Progression on ≥1 line

prior systemic chemo or within 12 months of (neo)adjuvant chemoOR

• Chemo-naïve: cisplatin ineligible per protocol criteria†

Regimen 2: 6 mg QD

R

Regimen 1: 10 mg/d for 7 days

on 7 days off Regimen 3*:8 mg QD with PD

Uptitration to 9 mg QD

n = 99

* Dose uptitration if ≥5.5 mg/dL target serum phosphate not reached by Day 14 and if no TRAEs† Ineligibility for cisplatin: impaired renal function or peripheral neuropathy

Screening for FGFR fusions/mutations on tissue by central lab

Primary endpoint: Objective response rate

Actual enrollment: 239

BLC2001: Erdafitinib Efficacy Data

Progression-Free Survival Overall Survival

ORR = 40% (additional 39.4% with SD) Duration of Response (median) = 5.6 mo

Loriot Y et al. N Engl J Med 2019;381:338-348.

Erdafitinib FDA Approval

• Accelerated approval for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (Apr 2019)


Erdafitinib - Toxicities

Siefker-Radtke AO et al. ASCO 2018;Abstract 4503.Courtesy of Peter H O’Donnell, MD

Erdafitinib – Key Toxicities

erdafitinib FDA label

5 WARNINGS AND PRECAUTIONS5.1 Ocular DisordersErdafitinib can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect. CSR/RPED was reported in 25% of patients treated with Erdafitinib, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued Erdafitinib.Dry eye symptoms occurred in 28% of patients during treatment with Erdafitinib and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.Withhold Erdafitinib when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)].5.2 HyperphosphatemiaIncreases in phosphate levels are a pharmacodynamic effect of Erdafitinib [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with Erdafitinib. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8 –116) after initiating Erdafitinib. Thirty-two percent of patients received phosphate binders during treatment with Erdafitinib.


Erdafitinib Dosing, and Adjustments• Recommended starting dose is 8 mg (two 4 mg tablets) orally once daily, with

dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate levels and tolerability at 14–21 days.

• Assess serum phosphate levels 14–21 days after initiating. Increase erdafitinibto 9 mg once daily if serum phosphate level is <5.5 mg/dl (and there are no ocular disorders or ≥Grade 2 adverse reactions).

• Monitor phosphate levels monthly for hyperphosphatemia.

erdafitinib FDA label


62-year-old man with PMH of Anxiety/Depression, Chronic Arthralgias and >30 Years History of Tobacco Use (from the practice of Ms Roethke)

• 3/2019 TURBT: High-grade MIBC, with focal invasion of muscularis propria and high-grade UC of prostatic urethra

• 6/2019: Completed neoadjuvant dose-dense MVAC x 3• Genomic testing: BRCA1 mutation, FGFR3 mutation• 7/2019: Radical cystoprostatectomy, b/l pelvic lymph node dissection, creation of ileal conduit

– Pathology: Residual 5.5-cm bladder tumor, micropapillary type with invasion to perivesicalsoft tissue, 4+ nodes

– Wound infection and abcess, distress and anger related to ostomy• 10/2019 CT: Normal• 12/2019: New bone metastases (see scan)• 1/2020: SBRT to T12• Erdafitinib

– Transient, mild mouth sores– Developed CSR, erdafitinib held until improvement then re-started at reduced dose

• 3/2020: Improvement on bone scan; improvement in pain and general well-being

62-year-old man (from the practice of Ms Roethke)

12/2019: New Bone Mets• Intense uptake in T12 vertebral body• Right ischial tuberosity• Right pubic bone• Left iliac bone posteriorly

Agenda







Module 5: Antibody-Drug Conjugates in UBC

When was the last time you encountered a patient with bladder cancer receiving enfortumab vedotin?






f. I have not encountered a patient with bladder cancer receiving enfortumab vedotin in my practice

figure adapted from creativebiolabs.net

Enfortumab Vedotin Proposed Mechanism of Action

MMAE = monomethyl auristatin E

Inhibit


Enfortumab Phase II Study Design(EV-201)

adapted from Petrylak et al., presented at ASCO 2019

ORR=objective response rateBICR=blinded independent central reviewDOR=duration of responseCourtesy of Peter H O’Donnell, MD

Enfortumab Efficacy Data• 44% ORR

Ø12% CRØ32% PR

• 84% of evaluable patients showed tumor reduction

• Median DOR = 7.6 mos

• Median PFS = 5.8 mos• Median OS = 11.7 mos

Rosenberg et al., JCO (2019)Rosenberg et al., JCO (2020)

Efficacy data mirror those from phase I study of n=155 UC patients


FDA Approval of EV

• For adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting (Dec 18, 2019)

fda.govCourtesy of Peter H O’Donnell, MD

EV - Tolerability

Rosenberg et al., JCO (2019)Courtesy of Peter H O’Donnell, MD

Enfortumab – Key Toxicities

adapted from Petrylak et al., presented at ASCO 2019 Courtesy of Peter H O’Donnell, MD

Enfortumab vedotin 1.25 mg/kg + pembrolizumab (200 mg) in 1L cisplatin-ineligible la/mUCpatients (N=45)

Dose Escalation1

enfortumabvedotin +

pembrolizumab


(n=5)

Patient Population

Locally Advanced

or Metastatic Urothelial Carcinoma

Dosing: Enfortumab vedotin on days 1 and 8 and pembrolizumab on day 1 of every 3-week cycle

Enfortumab vedotin exposure:Comparable to enfortumab vedotinmonotherapy on 4-week schedule (Days 1, 8, and 15)2

Primary endpoints: safety and tolerability

Key secondary endpoints: dose-limiting toxicities, ORR, DOR, PFS, OS

EV-103 – First-line Cohorts of Enfortumab Vedotin + Pembrolizumab

Dose ExpansionCohort A

enfortumabvedotin +

pembrolizumab


(n=40)1 Not included in the current analysis: three 1L patients treated with EV 1 mg/kg + pembrolizumab 200 mg and two 2L patients

treated with EV 1.25 mg/kg + pembrolizumab 200 mg2 Rosenberg et al. J Clin Oncol. 2019;37(29):2592-600.

Rosenberg JE et al. GU Cancers Symposium 2020; Abstract 441.

Courtesy of Daniel P Petrylak, MD

Maximal Target Lesion Reduction by PD-L1 status and Objective Response Rate per Investigator

• Responses observed regardless of PD-L1 expression level Two patients did not have post-baseline response assessments before end-of-treatment: 1 withdrew consent and 1 died before any post-baseline response assessment. These patients are included in the full analysis set used to calculate ORR, but are not included in the figure above. Horizontal lines at positive 20% and negative 30% denote thresholds for target lesions for disease progression and response, respectively.

93% had tumor reductionConfirmed ORR

95% CI73.3% (33/45)

(58.1, 85.4)

Complete response 15.6% (7/45)

Partial response 57.8% (26/45)

Best Overall Response Per RECIST v 1.1 by investigator (N=45)

Rosenberg JE et al. GU Cancers Symposium 2020; Abstract 441.Courtesy of Daniel P Petrylak, MD

70-year-old man with PMH of CKD, T2DM, HTN, Hyperlipidemia (from the practice of Ms Roethke)

• 1/2017: High-grade UC of right distal ureter• 3/2017: Completed neoadjuvant MVAC x 3 à 5/2017: R nephroureterectomy

– Pathology: Residual 1-cm carcinoma invading muscularis, Node-negative• 6/2017: Rapidly progressive recurrent disease, with gastric outlet obstruction à gastrojejunostomy

– Pathology: Metastatic UC, marked peritoneal carcinamatosis• 7/2017: Pembrolizumab 200mg Q3W à remarkable response, no measurable disease

– 4/2018: Adrenal insufficiency, treatment discontinued– Observation x 16 months

• 8/2019: Perirectal recurrence– Pembrolizumab resumed but discontinued due to continued tumor growth

• 11-12/2019: SBRT• 4/2020 CT and MRI: Large mass invading bladder, rectum, seminal vesicles• Enfortumab vedotin

– Bright red rash/exfoliative dermatitis -- treatment held -- resolved

70-year-old man (from the practice of Ms Roethke)

Rash/Exfoliative Dermatitis After Starting Enfortumab Vedotin

Agenda







Module 6: Management of UBC in the Era of COVID-19

63-year-old man (from the practice of Ms Daskalova)

• Non-muscle-invasive BC à BCG

• 2/2018: Subsequent cystoscopy: Muscle-invasive BC à radical cystoprostatectomy and neobladder creation

– Pathology: pT2aN0 papillary urothelial carcinoma

• Surveillance

• Second scan: New 1.8-cm lung nodule at the RUL C/W metastatic urothelial cancer

• Gemcitabine plus split-dose cisplatin à worsening kidney function à Gemcitabine + carboplatin (cycles 2-3)

• Restaging imaging: PD

• FGFR tumor mutation

• 1/2019: Pembrolizumab à progressive disease à erdafitinib with good response

• Contracted COVID-19 and passed away

Thank you for joining us!

CNE (NCPD) credit information will be emailed to each participant tomorrow morning.

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